Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:13][C:12]=1[O:32][CH3:33].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:34])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:20])=[CH:13][C:12]=1[O:32][CH3:33]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1F
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of pentafluorophenyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxy-phenylacetate (314.8 mg, 0.650 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (146.2 mg, 0.619 mmol), Et3 N (103 ul, 0.743 mmol) in DMF (1.5 mL) was stirred for 1 hr at room temp. The mixture was diluted with Et2O, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure to afford methyl 2-[[1-[4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a crude pale yellow oil.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([C:13]([CH2:20][CH3:21])([C:17]([OH:19])=[O:18])[C:14]([OH:16])=[O:15])[CH3:12]>C1(C)C=CC=CC=1>[CH2:20]([C:13]([CH2:11][CH3:12])([C:17]([O-:19])=[O:18])[C:14]([O-:16])=[O:15])[CH3:21].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCC(CC)(C(=O)O)C(=O)O
Reactant: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCC(CC)(C(=O)[O-])C(=O)[O-]
Product: CCCC[Sn+2]CCCC
Yield: 97.6 %

Procedure:
A mixture of 300 grams of dibutyltin oxide, 193 grams of diethylmalonic acid, and 500 ml. of toluene was refluxed for 1 hour. There was collected 21 grams of water in a Dean Stock trap by azeotropic distillation. The reaction mixture was then filtered while hot and allowed to cool to ambient temperatures. Removal of the solvent in vacuo provided 460 grams (98% yield) of dibutyltin diethylmalonate as a white crystalline solid. The identity of the product was confirmed by NMR, IR and FD-MS analysis.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:26]([O:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: C=C1CC(=O)O1
Reactant: OCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (2.52 mmol) of 2,2-diphenylethanol was dissolved in 10 ml of toluene. 382 mg (3.78 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature for 1 hour. 386 mg (3.03 mmol) of diketene was added to the obtained mixture under cooling with ice, and then they were stirred under heating at 100° C. for 2 hours. After the addition of saturated aqueous sodium hydrogencarbonate solution followed by the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the unpurified title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11].[OH-].[K+]>CCO.O.C(OCC)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)(C)c1cccc(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C(=O)O)c1cccc(Cl)c1Cl
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A mixture of methyl 2-(2,3-dichlorophenyl)-2-methylpropanoate (5.50 g, 22.3 mmol) and KOH (6.24 g, 111 mmol) in EtOH/water (5:1, 150 mL) in a 500 mL round bottom flask, was heated at 95° C. for 18 hours. The solution was diluted with diethyl ether (200 mL), and washed with 1N NaOH(aq) (3×75 mL). The aqueous solution was made acidic (pH=2) with concentrated HCl. The mixture was then extracted with EtOAc (3×100 mL), and the combined organic layers were washed with deionized water (100 mL) and with brine (75 mL). The organic layer was then dried over MgSO4, concentrated, and dried in vacuo. The crude product was purified by flash column chromatography (silica, 0-100% DCM in hexane) to give the title compound (4.1338 g). MS m/e=233 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][S:9]2(=[O:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16].[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:15]([C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH2:10][S:9]4(=[O:13])=[O:14])=[CH:7][C:2]=3[NH:1][C:31](=[O:33])[CH3:32])=[O:16])[CH2:22][CH2:21]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N)CC2)c(C)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1

Procedure:
Using [2-amino-4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (300 mg) described in Example 136 and acetyl chloride (0.07 mL) and by the reaction and treatment in the same manner as in Example 107, the title compound (279 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH2:31]OS(C)(=O)=O)=[N:28][N:27]=2)=[C:22]([C:37]([F:40])([F:39])[F:38])[CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]2[C:6]=1[N:7]=[CH:8][N:9]([CH2:31][C:29]1[S:30][C:26]([C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][C:22]=3[C:37]([F:40])([F:38])[F:39])=[N:27][N:28]=1)[CH:10]=2
Reactant: Fc1ccccc1-c1[nH]c2cncnc2c1Br
Reactant: COc1ccc(-c2nnc(COS(C)(=O)=O)s2)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Cn3cnc4c(Br)c(-c5ccccc5F)nc-4c3)s2)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
A solution of 7-bromo-6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (152 mg, 0.52 mmol) and methanesulfonic acid 5-(4-methoxy-2-trifluoromethylphenyl)-[1,3,4]thiadiazol-2-ylmethyl ester (211 mg, 0.57 mmol) were stirred in 2 mL DMF at 65° C. for 14 h. The solution was then heated to 85° C. for 4 h and cooled to rt. The resulting solution was filtered and purified by HPLC (10-70% MeCN/H2O with 1% formic acid). Lyophilization of the pure fractions gave 103 mg (0.183 mmol, 35% yield) of the titled compound. 1H NMR (DMSO-d6): 9.15 (s, 1H), 8.96 (s, 1H), 7.72 (d, 1H), 7.64 (t, 1H), 7.55 (q, 1H), 7.43 (s, 1H), 7.32-7.42 (m, 3H), 6.23 (s, 2H), 3.92 (s, 3H). LC-MS calculated for C23H14BrF4N5OS 563.00, found 564.35 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B([O-])=O.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCCOc1cc(C=O)ccc1OCc1ccccc1
Agent: O=B[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCCCOc1cc(CO)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 31 g of 4-benzyloxy-3-(3-methoxypropyloxy)-benzaldehyde in 530 ml of ethanol/water=8:2 is added dropwise to a suspension, stirred at 0° C., of 11.74 g of sodium boranate in 530 ml of a mixture of ethanol/water=8:2. The reaction mixture is stirred for one hour at 0° C. and is then concentrated by evaporation. The residue is partitioned between diethyl ether and water. The combined organic phases are dried over sodium sulfate and concentrated by evaporation, and the residue is purified by FC (100 g of silica gel, dichloromethane/diethyl ether=1:1), yielding the title compound: Rf (dichloromethane/diethyl ether=1:1)=0.43.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[C:16]([CH3:17])=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:10]=1[CH:11]=O>CCO.Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[C:3]2[C:4](=[O:7])[C:5](=[CH:11][C:10]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[C:16]([CH3:17])[C:9]=3[CH3:8])[CH2:6][O:1][CH2:2]2)=[C:9]([CH3:8])[C:16]=1[CH3:17]
Reactant: O=C1CCOCC1
Reactant: COc1ccc(C=O)c(C)c1C
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=C2COCC(=Cc3ccc(OC)c(C)c3C)C2=O)c(C)c1C
Yield: 38.6 %

Procedure:
A solution of 6.0 g (0.06 mole) of tetrahydro-4H-pyran-4-one, 21.6 g (0.13 mole) of 2,3-dimethyl-p-anisaldehyde in 75 ml of EtOH and 10 ml of concentrated HCl is stirred and heated at reflux for 3 hours. The product gradually precipitates during this period. After cooling, this material is filtered and treated with ether to give 9.1 g (39%) of yellow crystals, m.p. 225°-227°.
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: NC1CCCC1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)NC4CCCC4)cc3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 25 ml round bottom flask was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid (200 mg, 0.48 mmol), cyclopentyl amine (85 mg, 1 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluroniumtetrafluoroborate (321 mg, 1 mmol), diisopropylethylamine (0.34 ml, 2 mmol) in dimethylformamide (5 ml), under nitrogen. The reaction mixture was stirred at room temperature for 18 hours and then was diluted with ethyl acetate (40 ml), washed with a saturated sodium hydrogen carbonate aqueous solution (40 ml) and brine (40 ml). The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane to afford the title compound. 1H NMR (DMSO-d6): 1.60-1.65 (4H, m), 1.70-1.80 (2H, m), 1.95-2.10 (5H, m), 2.20-2.30 (2H, m), 3.90-4.00 (4H, s), 4.30-4.35 (1H, m), 5.35-5.40 (1H, s), 7.70-7.75 (2H, d), 8.00-8.05 (2H, d), 8.45-8.50 (1H, d), 9.3 (1H, s). MS (ES+): 450.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:12][CH2:13][C@:14]1([CH2:28][O:29][CH3:30])[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1.Cl[C:32]([O:34][CH3:35])=[O:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[CH3:35][O:34][C:32]([C@@:15]12[CH2:12][CH2:13][C@:14]1([CH2:28][O:29][CH3:30])[CH2:18][N:17]([C@@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:16]2=[O:27])=[O:33]
Reactant: COC[C@]1(CCBr)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@]12CC[C@@]1(C(=O)OC)C(=O)N([C@H](C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.3 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (13.4 mL, 13.4 mmol) was added to a solution of (4S)-4-(2-bromoethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.07 g, 6.08 mmol) and methyl chloroformate (0.493 mL, 6.38 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at −70° C. The mixture was stirred for 14 hours while gradually heating to room temperature. The reaction solution was cooled to 0° C. A 10% citric acid solution (20 mL) was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and water (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→2:1) to give 1.53 g (79%) of the title compound as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:20])([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21](NC(C)C)([CH3:23])[CH3:22].C(Br)C=C.C(OCC)(=O)C>C(#N)C>[CH2:23]([O:15][C:14]([C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=1)[O:10][C:8]([CH3:20])([CH3:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH:21]=[CH2:22]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Solvent: C=CCBr
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-(1-tert-Butoxycarbonyl-1-methylethoxy)benzoic acid (14.92 g, 53.22 mmol) was dissolved in acetonitrile (60 mL). Subsequently, diisopropylamine (8.25 g, 63.87 mmol) was added thereto. Thereafter, allyl bromide (12.87 g, 106.45 mmol) was added dropwise, and the mixture was stirred for five hours at room temperature. Ethyl acetate was added for extraction. Washing was performed sequentially with water and saturated brine, followed by drying over magnesium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby a colorless oil was obtained (11.59 g, 36.19 mmol, 67.9%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CCCCCC.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1ccncc1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4ccncc4)c3cc2OC)c1
Yield: 34 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (78 mg, 0.12 mmol) with 4-aminopyridine (19 mg, 0.20 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 34% yield (29 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14].C(O)C>CCCCCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.CCOCC>[F:6][C:7]1[CH:8]=[C:9]([C@H:15]2[CH2:20][CH2:19][C@H:18](/[CH:21]=[CH:1]/[CH2:2][CH2:3][CH3:4])[CH2:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: [Li]CCCC
Reactant: N#Cc1ccc(C2CCC(C=O)CC2)cc1F
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.4 ml of 1.7M n-butyllithium in hexane are added, with stirring and under an atmosphere of nitrogen, to a suspension of 5.4 g of n-butyltriphenylphosphonium bromide in 100 ml of ether. After 30 minutes the orange solution is cooled to -40° and 2.1 g of 4-(3-fluoro-4-cyanophenyl)-cyclohexanecarbaldehyde in 20 ml of ether are added. After stirring for 2 hours at -40°, 60 ml of ethanol are added dropwise. The reaction mixture is then allowed to warm up to room temperature, is stirred for one hour and worked up in the customary manner. 2-fluoro-4-[trans-4-(trans-1-pentenyl)-cyclohexyl]-benzonitrile is obtained after isomerisation in the customary manner analogously to European Published Application No. 0,122,389.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([CH2:43][OH:44])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([CH2:43][OH:44])=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1CO
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(CO)c(OC(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and [3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methanol (Stage 190.1.1) to give the title compound as a white solid. (HPLC: tR 2.19 min (Method A); M+H=459 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.27-8.23 (m, 1H), 8.15-8.10 (m, 2H), 8.03-7.98 (m, 1H), 7.62-7.59 (m, 1H), 7.40-7.37 (m, 1H), 4.84 (br, 1H), 4.76 (hp, 1H), 4.55 (s, 2H), 3.88 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H), 1.36-1.31 (m, 6H))
Reaction SMILES: C1(CO[C:6]2[C:7](OC)=[CH:8][C:9](C)=[C:10]([C:12](=[O:21])[C:13]3[C:18](Cl)=[CH:17][CH:16]=[CH:15][C:14]=3Cl)[CH:11]=2)CC1.[CH3:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-:30].[K+].[K+]>C(O)C>[CH2:27]([O:30][C:9]1[CH:8]=[CH:7][CH:6]=[CH:11][C:10]=1[C:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[CH2:26][CH3:25]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1OCC1CC1
Reactant: CCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCOc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-dichloro-5'-hydroxy-4'-methoxy-2'-methylbenzophenone (Compound 5; 1.0 g, 3.2 mmol), n-propyl bromide (0.5 g, 4 mmol), potassium carbonate (2.8 g, 20 mmol) and ethanol (10 ml) is stirred for 6 h at 80° C., filtered and the filtrate is evaporated in vacuo. The residue is applied onto a flash chromatography column (silica gel, 30 g). Elution with toluene (750 ml) yields Compound 6 as a brown oil, 800 mg, (70.7% y) which slowly crystallizes (mp 73°-75° C.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=2)[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH:22]=3)[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: CC(C)n1cc(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)c2)cn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)c2)cn1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
59 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)pyridine-2-amine, 19 mg of 2-aminopyrazine, 16 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, mg of sodium t-butoxide and 9 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 5 ml of degassed toluene, and the mixture was stirred at 85° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 40 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 30 mg of the objective compound as brown powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][C:38]1[C:46]2[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[CH:48]=3)=[N:44][C:43]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[N:42][C:41]=2[S:40][C:39]=1[C:60](O)=[O:61]>C(Cl)Cl.CN(C=O)C>[C:10]([NH:14][C:60]([C:39]1[S:40][C:41]2[N:42]=[C:43]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[N:44]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[CH:48]=3)[C:46]=2[C:38]=1[NH2:37])=[O:61])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)O)c(N)c23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Reaction time: 3 h

Procedure:
DIPEA (15.3 ml), tert-butylamine (9.3 ml) and TBTU (14.1 g) were added to a mixture of 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 31(f), 13.3 g) in a mixture of DCM (250 ml) and DMF (50 ml) under a nitrogen atmosphere. After 3 h at room temperature, the mixture was diluted with DCM and washed with sat. aq. NaHCO3, 0.1N aq. HCl and sat. aq. NaCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, using heptane/EtOAc=3/7 to 1/1 (v/v) as eluent.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:10][C:9]([S:11]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])(=[O:13])=[O:12])=[CH:8][CH:7]=2)=[N:2]1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccon2)s1
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccon3)s2)c1
Yield: 55 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 5-isoxazol-3-ylthiophene-2-sulfonyl chloride (13.7 mg, 0.055 mmol) and 3-aminobenzoic acid (6.9 mg, 0.050 mmol). The title compound was obtained in 55% yield (9.6 mg). MS (ESI+) calcd mass for C14H10N2O5S2 350.003113, found 350.002783.